The taking into account and treatment of pain are essential aspects of improving the quality of life of patients. Pain affects a considerable number of individuals, about 60 million in Europe each year, which represents an annual cost of 1 billion dollars in analgesic medicaments for treating said pain. The amounts spent annually throughout the world on analgesic medicaments can be evaluated at approximately 25 billion dollars, and should reach 42 billion in 2010. Pain is divided up into two categories: acute pain and chronic pain. Acute pain corresponds to rapid and brief pain which is limited over time. Conversely, chronic pain is a persistent pain which can be linked, for example, to hyperalgesia, and which constitutes an enormous disease burden, affecting approximately 20% of adults and 50% of the elderly population.
The treatment of pain is based essentially on the prescription of anti-inflammatories, whether they are nonsteroidal (NSAIDs) or steroidal (corticoids), and of weak or strong opiates. NSAIDs form the therapeutic class most widely prescribed throughout the world, owing to their great efficacy both on inflammation and on pain itself. They are used in all types of inflammatory pain, whether acute or chronic [Bertin and Vergne-Salle, 2007] [1]. When NSAIDs and/or corticoids are not sufficient to relieve inflammatory pain, the prescribing physician combines a non-anti-inflammatory analgesic, for example paracetamol, weak opioids (codeine, tramadol), and, if the pain continues to be resistant to the treatment, strong opioids (morphine, oxycodone, fentanyl) [Gutstein & Akil, 2006] [2].
While NSAIDs are very effective, they nevertheless remain great purveyors of adverse side effects. Among the most standard adverse side effects, digestive effects are very frequent and limit the use of NSAIDs in many clinical situations. There are also renal, cutaneous, mucosal, allergic and respiratory, hematological, hepatic and, finally, neurosensory and psychological adverse side effects [Bertin and Vergne-Salle, 2007, mentioned above] [1]. In addition, NSAIDs are not effective in all types of pain. Opioids also play a major role in combating pain, but can cause hallucinatory phenomena and cardiorespiratory depression. Analgesics can also be a source of dependence, for instance morphine, methadone, etc., dependence. There are also cases of habituation to analgesics, that is to say the dose necessary to obtain a constant effect must be increased. This habituation increases over time and therefore leads to the need to increase the doses and can lead to ineffectiveness of the medicament. Indeed, the dose necessary to relieve pain can become greater than the toxic dose of said medicament. Finally, treatment with opioids can also be associated with adverse effects such as severe constipation or hyperalgesia when the treatment is stopped (post-operative pain, for example) [Gutstein & Akil, 2006, mentioned above; Bannister & Dickenson, 2010] [2, 3].
Despite the diversity of the existing therapeutic arsenal, many types of pain remain relatively insensitive to the known analgesics, such as neuropathic pain following damage to the nervous system (50% of patients experience no relief), chronic visceral pain such as irritable bowel syndrome or chronic inflammatory bowel disease, fibromyalgia, pain associated with cancers and bone metastases, etc. [Yennurajalingam et al., 2004; Mizoguchi et al., 2009] [4, 5].
In this context, the discovery of novel analgesics compensating for these deficiencies and drawbacks and/or novel analgesic targets should therefore represent real progress.
Research in the pharmaceutical industry on pain has over the past few years resulted only in a few limited developments. Mention may, for example, be made of triptans for migraine and certain novel medicaments of which the use still remains limited, such as the combination of tetrahydrocannabinol and cannabidiol for cancer-related and neuropathic pain. In fact, the progress made over the last two decades comes essentially from a better use and adjustments of the dosage of the available analgesics. None of the major families of these analgesics has a benefit/risk ratio which is optimal, because of a limited efficacy and/or considerable side effects.
Among the molecular targets identified over the past few years, ion channels hold a particularly important place because they are directly involved in the detection and transmission of pain signals by sensory and central neurons. ASIC channels (Acid Sensing Ion Channels) are cationic channels activated by acidification of the extracellular medium (extracellular acidosis) [Waldmann & Lazdunski, 1998; Wemmie et al., 2006; Lingueglia et al., 2007] [6, 7, 8]. Thus far, four genes encoding at least seven subunits (ASIC1a, ASIC1b, ASIC1b2, ASIC2a, ASIC2b, ASIC3 and ASIC4) have been identified in mammals. Functional ASIC channels result from the association of various ASIC subunits as trimers [Jasti et al. 2007] [9] resulting in homomeric or heteromeric channels [Lingueglia et al., 1997; Benson et al., 2002; Hesselager et al., 2004] [10, 11, 12]. ASIC channels are essentially expressed in nociceptive sensory neurons of the peripheral nervous system and in central nervous system neurons [Waldmann et al., 1997a; Lingueglia et al, 2007, mentioned above; Noel et al., 2010] [13, 8, 14]. Although the ASIC1a and ASIC2 isoforms are present in both the central nervous system and the peripheral nervous system, the expression of the ASIC1b and ASIC3 isoforms is restricted to sensory neurons [Waldmann et al., 1997b; Bassler et al., 2001; Chen et al., 1998] [15, 16, 17].
It has been postulated that the ASIC channels expressed by sensory neurons, and in particular the ASIC3 channel, are capable of detecting extracellular acidifications that may develop during ischemia, inflammation, a hematoma, a fracture, a lesion, a surgical procedure (post-operative pain), or the development of certain tumors [Reeh and Steen, 1996] [18]. As it happens, it has been known for several years now that extracellular acidosis causes pain [Steen et al., 1995a; Issberner et al., 1996] [19, 20], and experiments carried out on healthy human volunteers [Ugawa et al., 2002; Jones et al., 2004] [21, 22] have shown the involvement of ASIC channels in acidic skin pain by means of amiloride and certain NSAIDs, which are nonspecific inhibitors of ASIC channels [Waldmann et al., 1997a, mentioned above; Voilley et al., 2001] [13, 23]. The important role of certain ASIC channels expressed in central nervous system neurons in neuronal activity (synaptic plasticity of the hippocampus, of the amygdala) and the neuromodulation of the transmission of pain information (ASIC 1a channels) by spinal cord neurons has also been demonstrated [Noel et al., 2010] [14].
Until recently, the repertoire of active ligands capable of inhibiting ASIC channels was mainly limited to amiloride, to certain NSAIDs and to the compound A-317567 [Dubé et al., 2005] [24]. However, none of these molecules is absolutely specific for ASIC channels or for a particular ASIC subunit. With the aim of identifying effectors specific for ASIC channels, a very large number of scorpion, bee, spider, snake or sea anemone venoms have been screened. Recently, two animal peptide toxins, PcTx1 and APETx2, have been identified which inhibit homomeric ASIC1a channels and the channels containing the ASIC3 subunit, respectively [Escoubas et al., 2000; Diochot et al., 2004] [25, 26]. The peripheral (subcutaneous) injection of APETx2 induces an analgesic effect on inflammatory and acidic pain in rats [Deval et al., 2008] [27] and on post-operative pain in rats after intra-operative application of APETx2 [Deval et al., J. Neurosci., 31(16): 6059-6066, 2011] [36], while the central injection of PcTx1 induces a powerful analgesic effect in mice [Mazzuca et al., 2007] [28]. The analgesic effects of these two toxins have made it possible to demonstrate the involvement in ASIC channels in the perception and transmission of pain information.
There is therefore a real need to identify other effectors specific for ASIC channels or for a particular ASIC subunit, capable of exhibiting an analgesic effect while at the same time compensating for the deficiencies, drawbacks and obstacles of the prior art analgesics.